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Dendritic cells prime natural killer cells by trans-presenting interleukin 15.

ABSTRACT: Natural killer (NK) cells are important effector cells in the control of infections. The cellular and molecular signals required for NK cell activation in vivo remain poorly defined. By using a mouse model for the inducible ablation of dendritic cells (DCs), we showed that the in vivo priming of NK cell responses to viral and bacterial pathogens required the presence of CD11c(high) DCs. After peripheral Toll-like receptor (TLR) stimulation, NK cells were recruited to local lymph nodes, and their interaction with DCs resulted in the emergence of effector NK cells in the periphery. NK cell priming was dependent on the recognition of type I IFN signals by DCs and the subsequent production and trans-presentation of IL-15 by DCs to resting NK cells. CD11c(high) DC-derived IL-15 was necessary and sufficient for the priming of NK cells. Our data define a unique in vivo role of DCs for the priming of NK cells, revealing a striking and previously unappreciated homology to T lymphocytes of the adaptive immune system.

SUBMITTER: Lucas M

PROVIDER: S-EPMC2084390 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Dendritic cells prime natural killer cells by trans-presenting interleukin 15.

Lucas Mathias M Schachterle William W Oberle Karin K Aichele Peter P Diefenbach Andreas A

Immunity 20070329 4

Natural killer (NK) cells are important effector cells in the control of infections. The cellular and molecular signals required for NK cell activation in vivo remain poorly defined. By using a mouse model for the inducible ablation of dendritic cells (DCs), we showed that the in vivo priming of NK cell responses to viral and bacterial pathogens required the presence of CD11c(high) DCs. After peripheral Toll-like receptor (TLR) stimulation, NK cells were recruited to local lymph nodes, and their ...[more]

PMID: 17398124

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Project description:Natural killer (NK) cells belong to the first line of host defense against infection and cancer. Cytokines, including interleukin-15 (IL-15), critically regulate NK cell activity, resulting in recognition and direct killing of transformed and infected target cells. NK cells have to adapt and respond in inflamed and often hypoxic areas. Cellular stabilization and accumulation of the transcription factor hypoxia-inducible factor-1? (HIF-1?) is a key mechanism of the cellular hypoxia response. At the same time, HIF-1? plays a critical role in both innate and adaptive immunity. While the HIF-1? hydroxylation and degradation pathway has been recently described with the help of mathematical methods, less is known concerning the mechanistic mathematical description of processes regulating the levels of HIF-1? mRNA and protein. In this work we combine mathematical modeling with experimental laboratory analysis and examine the dynamic relationship between HIF-1? mRNA, HIF-1? protein, and IL-15-mediated upstream signaling events in NK cells from human blood. We propose a system of non-linear ordinary differential equations with positive and negative feedback loops for describing the complex interplay of HIF-1? regulators. The experimental design is optimized with the help of mathematical methods, and numerical optimization techniques yield reliable parameter estimates. The mathematical model allows for the investigation and prediction of HIF-1? stabilization under different inflammatory conditions and provides a better understanding of mechanisms mediating cellular enrichment of HIF-1?. Thanks to the combination of in vitro experimental data and in silico predictions we identified the mammalian target of rapamycin (mTOR), the nuclear factor-?B (NF-?B), and the signal transducer and activator of transcription 3 (STAT3) as central regulators of HIF-1? accumulation. We hypothesize that the regulatory pathway proposed here for NK cells can be extended to other types of immune cells. Understanding the molecular mechanisms involved in the dynamic regulation of the HIF-1? pathway in immune cells is of central importance to the immune cell function and could be a promising strategy in the design of treatments for human inflammatory diseases and cancer.

Dataset Information

Dendritic cells prime natural killer cells by trans-presenting interleukin 15.

Publications

Dendritic cells prime natural killer cells by trans-presenting interleukin 15.

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